title: Stability and structural recovery of the tetramerization domain of p53-R337H mutant induced by a designed templating ligand.
abstract: Protein p53 is a transcription factor crucial for cell cycle and genome integrity. It is able to induce both cell arrest when DNA is damaged and the expression of DNA repair machinery. When the damage is irreversible, it triggers apoptosis. Indeed, the protein, which is a homotetramer, is mutated in most human cancers. For instance, the inherited mutation p53-R337H results in destabilization of the tetramer and, consequently, leads to an organism prone to tumor setup. We describe herein a rational designed molecule capable of holding together the four monomers of the mutated p53-R337H protein, recovering the tetramer integrity as in the wild-type structure. Two ligand molecules, based on a conical calix[4]arene with four cationic guanidiniomethyl groups at the wider edge (upper rim) and hydrophobic loops at the narrower edge (lower rim), fit nicely and cooperatively into the hydrophobic clefts between two of the monomers at each side of the protein and keep the tetrameric structure, like molecular templates, by both ion-pair and hydrophobic interactions. We found a good agreement between the structure of the complex and the nature of the interactions involved by a combination of theory (molecular dynamics) and experiments (circular dichroism, differential scanning calorimetry and (1)H saturation transfer difference NMR).
authors.affiliation: Institute for Research in Biomedicine, Parc Científic de Barcelona, Baldiri Reixac, 10, 08028 Barcelona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Gordo
authors.forename: Vera
authors.initials: V
authors.lastname: Martos
authors.forename: Eva
authors.initials: E
authors.lastname: Santos
authors.forename: Margarita
authors.initials: M
authors.lastname: Menéndez
authors.forename: Carles
authors.initials: C
authors.lastname: Bo
authors.forename: Ernest
authors.initials: E
authors.lastname: Giralt
authors.forename: Javier
authors.initials: J
authors.lastname: de Mendoza
mesh_terms: D047250:Calixarenes / Q000737:chemistry*; D019281:Dimerization; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D020125:Mutation, Missense; D010636:Phenols / Q000737:chemistry*; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D013057:Spectrum Analysis; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics*
chemical_list: D008024:Ligands; D010636:Phenols; D016159:Tumor Suppressor Protein p53; C121325:calix(4)arene; D047250:Calixarenes